Complementary pathways of necroptosis in recipient and donor lung tissue that drive primary lung allograft dysfunction

In this proposal, we aim to address a critical challenge in lung transplantation: primary graft dysfunction (PGD), a severe complication impacting over half of all lung transplant recipients and have a particularly high incidence in those with pre-existing acute lung injuries (ALI) or acute respiratory distress syndrome (ARDS). Despite lung

transplantation being a life-saving treatment for end-stage lung diseases, the high incidence of PGD significantly diminishes the long-term success and survival rates of these procedures. Our research is grounded in the discovery of the pivotal role played by intravascular nonclassical monocytes (NCM) in the donor lungs, which

are activated by damage-associated molecular patterns (DAMPs), especially high mobility group box 1 (HMGB1), initiating the cascade leading to PGD. Building on this foundation, our proposal hypothesizes that receptor-interacting protein kinase 3 (RIPK3)- dependent necroptosis in both the recipient's native lungs and the donor lungs is a key driver of PGD. This

hypothesis is supported by our preliminary data, which shows a sustained necroptotic process in the diseased lungs of recipients, particularly in cases of ALI and ARDS. We propose two specific aims to test this hypothesis: 1. Exploration of Autocrine Necroptosis in Recipient Lungs: The first aim focuses on the role of TNF-α

induced autocrine necroptosis in monocyte-derived alveolar macrophages within the acutely injured native lungs. We plan to investigate the release of HMGB1 as a result of this necroptosis and how it contributes to the activation of donor-derived NCM during lung transplantation. This study will provide

insights into the mechanisms through which pre-transplant lung conditions exacerbate the risk of PGD. 2. Investigation of Necroptosis in Donor Lungs: The second aim targets the necroptosis in donor lung tissue, specifically induced by mitochondrial reactive oxygen species (ROS) during the transplantation

process. We aim to identify the cell populations in the lung responsible for mitochondrial ROS generation in response to ischemia-reperfusion injury and delineate their role in the necroptotic process within the graft. This understanding is crucial for developing targeted interventions to mitigate the risk of PGD arising

from donor tissue conditions. The overarching goal of this research is to comprehensively understand and pharmacologically target the necroptotic pathways in both the donor and recipient lungs to reduce the incidence of PGD. This could positively impact the field of lung transplantation by significantly improving post-transplant outcomes. The successful

completion of this research could lead to the development of novel therapeutic strategies and biomarkers for predicting and managing PGD, thereby enhancing patient survival and quality of life following lung transplantation.